Neurodegenerative diseases are defined by the presence of ubiquitinated misfolded protein aggregates in the cytoplasm and/or nucleus of nerve cells. M. S. Forman, J. Q. Trojanowski, V. M.-Y. Lee, Nat. Med. 10, 1055 (2004). Although significant advances have resulted in the identification of the misfolded disease proteins in many neurodegenerative disorders, the identity of the ubiquitinated disease protein(s) in UBIs (defined here as ubiquitinated cytoplasmic, nuclear and dystrophic neuritic inclusions) in FTLD-U, the most common form of frontotemporal dementias (FTDs) (J. R. Hodges et al., Ann. Neurol. 56, 399 (2004); A. M. Lipton, C. L. White, 3rd, E. H. Bigio, Acta Neuropathol. (Berl) 108, 379 (2004); J. K. Johnson et al., Arch. Neurol. 62, 925 (2005); J. Shi et al., Acta Neuropathol. (Berl) 110, 501 (2005)), and amyotrophic lateral sclerosis (ALS) have remained enigmatic.
FTDs are clinically, genetically, and pathologically heterogeneous, and are the second most common cause of dementia under age 65 (G. M. McKhann et al., Arch. Neurol. 58, 1803 (2001); M. S. Forman et al., Ann. Neurol. 59, 952 (2006)). Clinically, FTDs present with progressive changes in social, behavioral, and/or language dysfunction (G. M. McKhann et al., Arch. Neurol. 58, 1803 (2001); D. Neary et al., Neurology 51, 1546 (1998); M. Grossman, J. Int. Neuropsychol. Soc. 8, 566 (2002)) and less commonly with parkinsonism or motor neuron disease (MND). J. R. Hodges et al., Ann. Neurol. 56, 399 (2004); C. Lomen-Hoerth, T. Anderson, B. Miller, Neurology 59, 1077 (2002). Conversely, ALS, a common form of MND, is often associated with FTD (C. Lomen-Hoerth, et al.) and UBIs as in FTLD-U (M. S. Forman et al., Ann. Neurol. 59, 952 (2006)). Thus, the clinical overlap and shared ubiquitin pathologies in FTLD-U and ALS syndromes suggest they represent different ends of a clinicopathological spectrum of the same neurodegenerative disorder similar to amyotrophic lateral sclerosis/parkinsonismdementia complex of Guam tauopathy. J. Q. Trojanowski et al., Exp. Neurol. 176, 1 (2002).
Although diverse neuropathology underlies the clinical syndrome of FTDs, genetic, immunohistochemical, and biochemical data are incorporated into its current nosology (G. M. McKhann et al., Arch. Neurol. 58, 1803 (2001)), which broadly divides cases into those with tau-positive inclusions (e.g., Pick's disease [PiD], corticobasal degeneration [CBD], progressive supranuclear palsy [PSP], etc.), versus FTLD-U with UBIs. M. S. Forman et al., Ann. Neurol. 59, 952 (2006). More than 30% of FTD patients have a positive family history as exemplified by those with autosomal dominant inheritance linked to chromosome 17. However, FTD with parkinsonism linked to chromosome 17 (FTDP-17) is usually associated with neurofibrillary tau pathology caused by pathogenic mutations in the microtubule associated protein tau (MAPT) (M. Hutton et al., Nature 393, 702 (1998); P. Poorkaj et al., Ann. Neurol. 43, 815 (1998)), which is designated here as FTDP-17T.
Additionally, a number of these FTDP-17 families do not develop tau pathology and lack MAPT gene mutations, but instead develop UBIs (designated as FTDP-17U). C. L. Lendon et al., Neurology 50, 1546 (1998); R. Rademakers et al., Mol. Psychiatry 7, 1064 (2002); I. R. Mackenzie et al., Brain 129, 853 (2006). Recently, mutations that result in premature termination of the coding sequence for progranulin (PGRN) were identified and shown to be the disease-causing gene in FTDP-17U. M. Baker et al, Nature. In press (2006). However, since PGRN is not incorporated into UBIs in FTDP-17U (id.), the identity of the disease protein in UBIs of sporadic and familial FTLD-U has remained enigmatic.
Ubiquitin-positive, tau- and α-synuclein-negative inclusions are hallmark lesions of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS), but the identity of the disease protein specific to either disorder has heretofore remained unknown.
Pathological heterogeneity in the distribution and morphological characteristics of UBIs could signify that different disease proteins underlie FTLD-U variants or that a single protein is differentially modified in the variants. D. M. Sampathu et al, Am. J. Pathol. In press (2006). For example, at least three FTLD-U subtypes have been identified: Type 1 with a predominance of long neuritic profiles in superficial cortical layers; Type 2 with UBIs mainly in superficial and deep cortical layers; Type 3 with signature ring-shaped UBIs and short neuritic profiles predominantly in superficial cortex. Id. Immunohistochemical analyses with novel monoclonal antibodies (MAbs), generated by immunization of mice with high Mr insoluble material prepared by biochemical fractionation of FTLD-U brains supports the distinction of these FTLD-U subtypes (id.), but these MAbs did not enable identification of the disease protein in the UBIs of FTLD-U (id.).